Multigene Kinase Network, Kidney Transport and Salt in Essential Hypertension

描述（由申请人提供）：原发性高血压是对公共卫生的主要威胁，影响全球超过10亿人，每年导致500万人的肾脏和心血管死亡和发病。像其他复杂的疾病一样，具有不同等位基因的多个基因和不同的环境压力被认为是导致这种疾病的原因。使用全基因组关联策略，我们最近确定了第一个原发性高血压易感基因STK 39（又名SPAK丝氨酸/苏氨酸激酶），阐明了一个新描述的多基因激酶网络和一个特定的环境触发因素-饮食盐-高血压的发生。本研究组和其他研究组的现有证据表明：1）STK 39与WNK基因的产物，即在一种罕见的高血压和高钾血症家族性疾病中突变的丝氨酸/苏氨酸激酶相互作用，以控制肾盐排泄和维持血压; 2）膳食钠和钾通过STK 39/WNK通路不同地触发信号传导以调节关键肾盐转运蛋白的活性，噻嗪类利尿剂敏感的氯化钠共转运蛋白（NCC）; 3）异常的STK 39信号获得引起NCC活性的不适当增加，导致钠潴留和高血压。在这里，我们汇集了一个多学科的团队，开发和应用新的转基因动物模型和试剂，以测试这些令人兴奋的新想法，基因-基因和基因-环境相互作用在高血压的发展，建立在我们最近的发现。这些新工具和知识的发展将揭示疾病的潜在分子和遗传机制。它还将提供急需的模型来研究和确定新的干预治疗策略。 公共卫生相关性：原发性高血压是对公共卫生的主要威胁，影响世界上超过10亿人，并且每年导致500万人的肾脏和心血管死亡和发病。像其他复杂的疾病一样，具有不同等位基因的多个基因和不同的环境压力被认为是导致这种疾病的原因。在这里，我们汇集了该领域的多学科专家团队，开发和应用新型转基因动物模型和试剂，以测试关于多激酶基因网络和特定环境触发因素-饮食盐-在高血压发生中的令人兴奋的新想法，建立在我们最近发现的STK 39激酶作为原发性高血压易感基因的基础上。

DESCRIPTION (provided by applicant): Essential hypertension is a major threat to public health, affecting over a billion people in the world and contributing to kidney and cardiovascular mortality and morbidity in 5 million people annually. Like other complex disorders, multiple genes with variant alleles and different environmental stresses are thought to contribute to the disease. Using a genome-wide association strategy, we recently identified the first essential hypertension susceptibility gene, STK39 (aka SPAK serine/threonine kinase), illuminating a newly described, multi-gene kinase network and a specific environmental trigger--dietary salt-- in the genesis of hypertension. Available evidence from our group and others suggests: 1) STK39 interacts with the products of the WNK genes, serine/threonine kinases that are mutated in a rare familial disorder of hypertension and hyperkalemia, to control kidney salt excretion and maintain blood pressure; 2) Dietary sodium and potassium differently trigger signaling through the STK39/WNK pathway to regulate the activity of a key renal salt transport protein, the thiazide diuretic sensitive sodium chloride co- transporter (NCC); 3) Aberrant gain-of-STK39 signaling causes an inappropriate increase in NCC activity, leading to sodium retention and hypertension. Here we bring together a mutlidisciplinary team to develop and apply novel transgenic animal models and reagents to test these exciting new ideas about gene-gene and gene-environment interactions in the development of hypertension, building on our recent discoveries. Development of these new tools and knowledge will shed light on the underlying molecular and genetic mechanisms of the disease. It also will provide much-needed models to study and identify new therapeutic strategies for intervention. PUBLIC HEALTH RELEVANCE: Essential hypertension is a major threat to public health, affecting over a billion people in the world and contributing to kidney and cardiovascular mortality and morbidity in 5 million people annually. Like other complex disorders, multiple genes with variant alleles and different environmental stresses are thought to contribute to the disease. Here we bring together a mutlidisciplinary team of experts in the field to develop and apply novel transgenic animal models and reagents to test exciting new ideas about a multi-kinase gene network and a specific environmental trigger--dietary salt--in the genesis of hypertension, building on our recent GWA discovery of STK39 kinase as an essential hypertension susceptibility gene.